The objective of this grant is to understand the influence of virus infection on the initiation of virus-specific CD8+ T cell immunity. Since cytotoxic T lymphocyte (CTL) responses are largely toward internal conserved molecules of influenza virus, our overall goal is to design a vaccine which can stimulate CD8+ T cell immunity to provide more effective heterotypic protection. Initiation of the virus-specific CD8+ T cell response is dependent on a number of bi-directional interactions between the T cell and the antigen presenting cell (APC). Our hypothesis is that influenza virus alters the level of expression of molecules on the APC, and consequently modifies the quality and quantity of immune response. Since dendritic cells (DC) are the primary APC that initiate an immune response we use either freshly-isolated DC, or DC cultured from bone-marrow to investigate the effect of influenza virus infection. Our specific aims are to (i) define the mechanism by which influenza virus alters the function of DC, and (ii) to determine the immune consequences of DC that are infected with influenza virus. We use alloreactive T cells as well as antigen-specific naive and memory CD8+ T cells to elucidate the mechanism used to alter DC in vitro and in vivo. The contribution of viral hemagglutinin (HA) and neuraminidase (NA), costimulators and adhesins to the altered T cell response is determined. The quality and quantity of the CD8+ T cell response is examined in the presence or absence of specific glycoproteins shown to alter DC function. This proposal is designed as an essential step towards the development of more effective influenza vaccine.